PONE-D-24-20978Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancerPLOS ONE

Dear Dr. Heo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I suggest to consider the comments of the reviewers to improve the quality of the manuscript with the main focus on methodological details, sub-group analysis and statistics. 

Please submit your revised manuscript by Aug 25 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Gernot Ortner

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

3. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a retrospective study of 45 patients who underwent LE following RCx for BCa. The success rate was 62.2%, and lymphatic complications after LE were noted in three patients. In MVA, maximal daily drainage of >1,000 mL/day and DM were independent factors associated with LE failure.

The paper is well-written with an appropriate methodology and a clear message.

Comments and questions:

Introduction:

1. When discussing LND extent in RCx, it would be beneficial to mention the results of the SWOG 1011 trial.

2. I recommend reporting further details on the management of lymphatic leakage in “bladder cancer” patients instead of presenting general data.

Methods:

1. Were all cystectomies performed with curative intent, or were there any palliative cases?

2. Please add details about LND. What methods were used for ligating the lymphatics (metal clips, bipolar, etc.)? How many drains in which locations were placed after the surgery?

3. Daily drainage < 300 mL/day has been the indication for drain removal. Please comment on this, as it is on the high side.

4. The primary and secondary outcomes should be clearly defined.

Results:

1. Given the number of cases, the continuous variables should be reported as median (IQR or range) instead of mean (SD).

2. Is there any data on baseline comorbidities (e.g., ASA, CCI, ECOG), length of hospital stay, and overall perioperative complications?

3. Among those who responded well to LE, what was the trend of lymphatic drainage before and after embolization?

Discussion:

1. The data reported on line 212 (77.6% successful drain removal) is a bit confusing.

2. Please highlight the pros and cons of LE over conservative management.

3. For those who are at higher risk for LE failure, what is your suggested strategy?

Reviewer #2: Dear Authors,

Thank you for submitting your manuscript. This study presents an interesting analysis of 45 patients who underwent lymphatic embolization after radical cystectomy. I appreciate the opportunity to review it. Below are my comments and suggestions for improvement:

- I would appreciate a more detailed description of the embolization procedure, providing more technical information.

- You only described perioperative variables of the cystectomy. Consider adding other variables, such as the quantity of embolizing fluid injected, etc.

- For the multivariate analysis, why did you set 1000 mL as a cutoff? Is there a study that defines that value as a predictor of lymphatic leakage? You should consider using a discrete value, for example, every 100 mL/day, to understand how the probability of the event increases with each increment.ù

Thank you again for your work and for allowing me to review your manuscript.

Reviewer #3: Shin and colleagues present a retrospective study on the outcome of lymphatic embolization (LE) in patients undergoing RC with PLND (standard PLND template) proximal to the common iliac bifurcation, inferior to the circumflex iliac vein and medial to the genitofemoral nerve. LE was performed if the daily catheter drainage exceeded 500 mL/day for >5 days despite conservative therapy. The authors excluded patients with lymphocele evident on CT before LE.

Patients were stratified by success vs. failure. Failure was defined as: 1) those who required drainage catheter placement >7 days after LE, 2) those who needed re-intervention before catheter removal, and 3) those who experienced adverse events associated with LE. LE was performed by injecting a mixture of N-butyl cyanoacrylate and ethiodized oil at a ratio of 1:1–1:4 into the inguinal LN.

Of 491 patients, 55 patients experienced a lymphocele with LE. 45 patients were included in this study. Of these, 28/45 were in the success group. The mean number of resected LN was 18.89 ± 9.53 and 20.94 ± 10.50 for the success and the failure group, respectively. The mean time from RC to LE was 8.50 ± 3.91 and 13.18 ± 17.22 days for the success and the failure group, respectively. Drainage catheters remained in place significantly longer in the failure group (3.54 ± 1.69 vs. 9.12 ± 5.12).

Secondary interventions in the failure group (n=17) comprised the need for a reintervention/-embolization, prolonged catheter, complications etc.

In the multivariable analysis, maximal daily drainage volume of >1,000 mL/d and diabetes were associated with clinical failure. The scientific English is good.

I have a few points to consider:

• The authors should describe the PLND template in more detail.

• What is the proportion of patients with lymphoceles that underwent LE?

• The authors excluded patients with lymphocele evident on CT before LE. What was the rationale for this?

• The authors state that (page 6, line 106): “Lymphatic leakage was diagnosed when radiographic evidence of leakage was found in lymphangiography“. Did all patients undergo lymphangiography?

• The authors excluded patients with evident lymphoceles on CT before LE. Why were those patients excluded? Why were not all patients included that underwent LE?

• The size and extent of the lymphoceles are poorly characterized. Please elaborate.

• How was correct catheter placement during drainage of the lymphocele verified?

• I suggest revising the statistics of the paper, adhering to the statistical outcome reporting guidelines provided by major urological journals

• How were the complications assessed? Was there a standardized approach?

• The confidence intervals in the multivariable analysis are incredibly large.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes.

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-24-20978R1Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancerPLOS ONE

Dear Dr. Heo,

Thank you for submitting the revised version of your manuscript to PLOS ONE. After careful consideration and in light of the reviewers' comments, we feel that your manuscript has merit to get published but requires some minute alterations prior to publication. Therefore, we invite you to submit a revised version of the manuscript that addresses these points raised.

Please submit your revised manuscript by Oct 13 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Mazyar Zahir, MD 

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

1. I believe that, given the small sample size and multiple limitations of the study, the conclusions drawn may overemphasize the benefits of lymphatic embolization (LE). I suggest revising the conclusion section of both the abstract and the main manuscript body ( line 323) to clarify that your findings are only suggestive of a possible effectiveness of LE in controlling post-operative lymphatic leaks after radical cystectomy.

2. The very high rate of clinical failure in the robotic surgical group warrants further elaboration. It appears that 3 out of 4 patients (75%) in this group experienced LE failure. This might suggest that the surgical team is less experienced with robot-assisted radical cystectomy (RARC) and typically performs surgeries in an open radical cystectomy (ORC) manner, potentially leading to more lymphatic manipulation and leaks (indicating a learning curve effect).

3. Another issue lies with the type of urinary diversion (UD). It was observed that 14 out of 45 patients (31.1%) underwent ureterocutaneostomy (UC), a simple UD associated with a much lower risk of lymphatic injury. However, UC is not commonly utilized in developed Western countries. This represents another limitation of your study, particularly in terms of the generalizability of your findings.

4. The definition of clinical success needs to be properly referenced.

5. I encourage the respected authors to undertake a thorough linguistic and grammatical revision of the manuscript, ideally in collaboration with a native English-speaking physician. Several sentences do not clearly convey their intended meaning. For example, the sentence in lines 271-272, "Here, we found that a maximal preprocedural drainage volume exceeding 1,000 mL/day was an independent predictor of LE success," implies that a higher preprocedural drainage volume correlates with higher success, whereas the opposite is true. The term "success" should be changed to "failure" here.

Additional lines requiring significant grammatical and linguistic revisions include lines 71-75, 81-86, 103-108, 164-172, 183-185, and 294-300.

6. Lines 84-86 and 89-90 discuss similar concepts regarding the prevalence of lymphatic complications. I recommend removing one of these sections to improve the flow of the introduction. The introduction is generally good but needs a comprehensive grammatical and linguistic revision.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to thank the authors for addressing all the comments appropriately. I have no further comments.

Reviewer #2: Dear Authors,

Thank you for submitting your revised manuscript. I appreciate the opportunity to review it after your improvements. I don’t have further comments on this paper.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Bignante Gabriele

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancer

PONE-D-24-20978R2

Dear Dr. Heo,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Mazyar Zahir, MD

Academic Editor

PLOS ONE